Acetyl-butyl-cis-1-propenyl phosphonate

ABSTRACT

A NEW CLASS OF CIS-1-PHOSPHINITE DERIVAIVES ARE DISCLOSED. THE PRODUCTS ARE USEFUL AS INTERMEDIATE IN THE PREPARATION OF ($) AND (-) (CIS-1,2-EPOXYPROPYL) PHOSPHONIC ACIDS WHICH HAVE UTILITY AS ANTIBIOTICS.

United States Patent U.S. Cl. 260-941 1 Claim ABSTRACT OF THE DISCLOSUREA new class of cis-l-propenyl-phosphinite derivatives are disclosed.These products are useful as intermediates in the preparation of (i) and(cis-1,2-epoxypropyl)phosphonic acids which have utility as antibiotics.

This application is a division of SN. 729,388, filed May 15, 1968, nowU.S. Pat. 3,625,982.

BACKGROUND OF THE INVENTION Although many valuable antibiotics have beendiscovered which are useful in the treatment of diseases, suchantibiotics are generally active against only a limited number ofpathogens or are rendered ineffective by the development ofantibiotic-resistant strains of pathogens. It is therefore importantthat new antibiotics be found which are active against a wide range ofpathogens as well as against resistant strains of pathogens.

Accordingly, this invention relates to the preparation of(cis-1,Z-epoxypropyl)phosphonic acid or mixtures thereof with itsdextrorotatory enantiomer which enantiomer has been found to be avaluable antibiotic exhibiting activity against various microorganismsand, in particular, against various gram-negative and gram-positivepathogens.

SUMMARY OF THE INVENTION In accordance with the present invention, it isfound that (cis-1,2-epoxypropyl)phosphonic acid is prepared by oxidationof (cis-1,2-epoxypropyl)phosphonous acid or the esters, halides andsalts thereof. Thus, (:t) (cis-1,2-epoxypropyl)phosphonic acid isprepared by oxidation of (i) (cis-l,2 epoxypropyl)phosphonous acid.Alternatively, :)(cis-l,2-epoxypropyl)phosphonous acid is separated intoits and enantiomers each of which are then subjected to oxidation toyield and (cis-l,2- epoxypropyDphosphonic acids.

In the ensuing description, teachings which are directed to thepreparation of salts of (cis-1,2-epoxypropyl)phosphonic acid areintended to include the free acid. Similarly, the oxidation of(cis-l,Z-epoxypropyl)phosphonous acid salts is intended to include thehalides and the free acid and esters thereof and intermediates used inthe preparation of (cis-l,2-epoxypropyl)phosphonous acid salts may be inthe free acid form or esters thereof or halides.

(Cis-1,2-epoxypropyl)phosphonic acid and its salts both in the (i) andforms are useful antimicrobial agents which are active in inhibiting thegrowth of both grampositive and gram-negative pathogenic bacteria. Theform and particularly its salts are active against Bacillus,Escherichia, Staphylococci, Salmonella and Proteus pathogens andantibiotic-resistant strains thereof. Illustrative of such pathogens areBacillus subtilis, Escherichia coli, Salmonella schottmuelleri,Salmonella gallinarum, Salmonella pullorum, Proteus vulgaris, Proteusmirabilis, Proteus morganii, Staphylococcus aureus and Staphylococcuspyogenes. Thus, (1 and (cis-1,2-epoxypropyl)phosphonic acid and itssalts can be used as antiseptic agents to remove susceptible organismsfrom pharmaceutical, dental "ice and medical equipment and other objectssubject to infection by such organisms. Similarly, they can be used toseparate certain microorganisms from mixtures of microorganisms. Saltsof (-)(cis-1,2 epoxypropyDphosphonic acid are also useful in treatmentof diseases caused by bacterial infections in man and animals and areparticularly valuable in this respect since they are active againstresistant strains of pathogens. These salts are especially valuablesince they are effective when given orally although they can also beadministered parenterally.

The salts of (i) (cis1,2-epoxypropyl)phosphonic acid are useful aspreservatives in industrial applications since they effectively inhibitundesirable bacterial growth in the white water used in paper mills andin paints, e.g. in polyvinyl acetate latex paint.

Additionally, the enantiomer is converted by procedures known to thoseskilled in the art to the enantiomers.

When (i) (cis-l,2-epoxypropyl)phosphonic acid or its salts or labileesters are used for combatting bacteria in man or lower animals, theymay be administered orally in a dosage form such as capsules or tablets,or in a liquid solution or suspension. These formulations may beprepared using diluents, granulating agents, preservatives, binders,flavoring agents and coating agents known to those skilled in thisparticular art. Alternatively, they may be administered parenterally byinjection in a sterile vehicle, and for this it is normal to use a saltthat is soluble in the liquid vehicle.

The (cis-1,2-epoxypropyl)phosphonic acid referred to herein rotatesplane-polarized light in a counterclockwise direction (to the left asviewed by the observer) when the rotation of its disodium salt ismeasured in water (5 concentration) at 405 mu.

The designation cis used in describing the 1,2-epoxypropyl phosphonicacid compounds means that each of the hydrogen atoms attached to carbonatoms 1 and 2 of the propylphosphonic acid are on the same side of theoxide ring.

In view of the above, it is an object of this invention to provide aprocess for preparing (cis-1,2-epoxypropyl) phosphonic acid.

Another object is to provide a process for preparing (cisl,2-epoxypropyl) phosphonic acid.

A further object is to provide novel phosphonous acid compounds andnovel intermediates useful in the preparation thereof.

DETAILED DESCRIPTION OF THE INVENTION The above objects and others whichwill become apparent to those skilled in the art are accomplished inaccordance with the present invention by subjecting to oxidation acis-phosphonous or cisthiophosphonous acid compound having the formulaewherein X represents hydroxy, thiol, hydrogen or Y and Y representshydrogen, halogeno or -OR, wherein R represents hydrogen or analiphatic, cycloaliphatic, aromatic or aromatic heterocyclic group.Where Y represents OH or SH, the compounds exist essentially in thetautomeric form of Formula IA and it is intended that salts of suchcompounds be included.

Thus, R represents a substituted or non-substituted alkyl group,preferably a lower alkyl group having from 1 to about 6 carbon atoms.Illustrative groups include methyl, ethyl, propyl, isopropyl, butyl,t-butyl, i-butyl, amyl, hexyl, acetoxymethyl, dimethylamino,diethylaminomethyl and the like.

Aromatic groups represented by R include substituted or non-substitutedaryl groups, for example, phenyl, naphthyl and substituted derivativesthereof such as tolyl, xylyl, cyanophenyl, nitrophenyl, halophenyl suchas chlorophenyl, anilino, biphenylyl, formylphenyl, hydroxyphenyl andthe like. Aralkyl groups included within the definition of R includesubstituted or non-substituted aralkyl groups such as benzyl, phenethyl,p-methylbenzyl and the like which may also contain additionalsubstituents such as halogen, e.g. ehloro, bromo, fiuoro, or cyano,nitro, hydroxy and the like.

Additionally, R represents substituted or non-substituted cycloalkylgroups, e.g. cyclopentyl, cyclohexyl and the like.

Further, R represents substituted or non-substituted alkenyl groupsincluding allyl, butenyl, pentenyl, hexenyl and the like which mayadditionally have substituents such as cyano, halogenyl and the like.

R also represents substituted or non-substituted alkynyl groups such aspropargyl, butynyl, hexynyl and the like which may have substituentssuch as cyano, halogeno and the like.

Further, R represents substituted or non-substituted cycloalkenyl groupssuch as cyclopentenyl, cyclohexenyl and the like.

Additionally, R represents aromatic heterocyclic groups containingoxygen, sulfur or nitrogen, e. g. pyridyl, thienyl, furyl, pyrryl andthe like.

Illustrative salts of compounds of Formula 1 where Y=OH include bothorganic and inorganic salts. Examples of such salts are inorganicmetallic salts such as sodium, aluminum, potassium, ammonium, calcium,magnesium, silver and iron salts. Organic salts that may be mentioned asrepresentative include salts with primary, secondary or tertiary aminessuch as monoalkylamines, dialkylamines, trialkylamines andnitrogen-containing heterocyclic amines. Representative examples aresalts with amines such as a-phenethylamine, diethylamine, quinine,brucine, lysine, protamine, arginine, procaine, ethanolamine, morphine,benzylamine, ethylenediamine, N,N-dibenzylethylenediamine,diethanolamine, piperazine, dimethylaminoethanol, 2-amino-2methyl-l-propanol, theophylline, esters of amino acids andN-methylglucamine. If desired, the basic moiety of the salt may be abiologically active amine such as erythromycin, oleandomycin ornovobiocin.

Where Y represents halogen, such halogen group may be chlorine, bromine,iodine or fluorine.

As stated above, the method of this invention comprises the oxidation ofcompounds having the structure of Formula I wherein (i)(cis-l,2-epoxypropyl)phosphonic acid is obtained. The particular productobtained upon direct oxidation of the compounds of Formula I will, ofcourse, depend on the specific compound being oxidized. Thus, oxidationof (i) (cis-1,2-epoxypropyl) phosphonous acid or (1-)(cis-l,2-epoxypropyl)thiophosphonous acid will directly yield(cz's-1,2-epoxypropyl) phosphonic acid, the oxidation state of thephosphorous atom having been increased during the oxidation reaction.Where, however, in Formula I Y represents an OR, a halogen group or asalt of an OH containing compound, the corresponding(cis-1,2-epoxypropyl)phosphonic acid ester, halide or salt will beobtained. If desired, the halide ester or salt derivative of (i)(cis-1,2-epoxypropyl)phosphonic acid may then be converted to free(cis-l,2-epoxypropyl)phosphonic acid.

The oxidation of the compounds of Formula I is conveniently carried outin aqueous medium. However, any solvent which is compatible with theoxidizing agent and in which the compound to be oxidized is partiallysoluble may be utilized. Thus, exemplary solvents are alcohols,especially lower alkanols, e.g. ethanol, butanol; cyclic ethers such asdioxane and tetrahydrofuran; dimethylformamide and the like. As statedabove, compatibility with the oxidizing agent is the main criterion inselecting a solvent. Thus, for certain oxidizing agents, e.g. mercuricchloride, an aliphatic hydrocarbon solvent such as pentanb or hexane issuitable.

The temperature of the oxidation reaction is not critical but thereaction is preferably conducted at from -10 to 60 C. or higher.

The oxidation of the compounds represented by Formula I to yield(cis-l,2-epoxypropyl)phosphonic acid is accomplished by a wide varietyof oxidizing agents. Thus, any oxidizing agent which will raise theoxidation state of the phosphorous atom in(cis-l,2-epoxypropyl)phosphonous acid is within the scope of thisinvention. Care must be taken, however, during oxidation to insure thatthe epoxide ring, which is unstable in higher acid media, is notdisrupted. Methods by which disruption of the epoxide bond is minimizedor eliminated include neutralization of the reaction mixture by theregulation of pH and the utilization of buffering solutions.

Typical oxidizing agents which are utilized in the process of thisinvention include air; ozone; Fehlings solution; inorganic and organicperacids such as perchloric acid, periodic acid, pertungstic acid,pervanadic acid, permolybdic acid, perphthallic and perbenzoic acid;perchlorates or persulfates such as sodium perchlorate, potassiumperchlorate or sodium persulfate; ceric sulfate; metal nitrates such assilver nitrate, mercuric nitrate, ceric nitrate; bismuthates such assodium bismuthate; pyrophosphates such as manganese pyrophosphate; metalcomplexes such as ammoniacal ceric nitrate or ammoniacal silver nitrate;metal oxides such as mercuric oxide, manganese dioxide, ceric oxide,silver oxide, arsenic oxide or supric oxide; metal acylates such as leadtetraacetate; metal tungstates such as sodium or potassium tungstate;halogens such as iodine, chlorine, bromine or fluorine; hypohalites suchas sodium or calcium hypohalite or t-butyl hypohalite; halogenates suchas sodium bromate or potassium iodate and the like; metal permanganatessuch as potassium permanganate; metal chromates such as potassiumdichromate; organic and inorganic peroxides such as dicumylperoxide,hydrogen peroxide and the like; organic hydroperoxides such as tbutylhydroperoxide, cumene hydr0- peroxide or anylene hydroperoxide; peroxyacids such as peroxytrifluoroacetic acid; inorganic acids such as nitricacid and the like. Preferred oxidizing agents are hydrogen peroxide,iodine, silver oxide and a mixture of hydrogen peroxide and sodiumtungstate.

In most instances, oxidation of (sis-1,2-epoxypropyl) phosphonous acidand the indicated derivatives thereof will normally yield the salts of(cz's 1,2-epoxypropyl) phosphonic acid due to the work-up proceduresnecessary for product recovery. Actually it is preferred that theproduct be recovered in the salt form.

Those salts which are pharmaceutically acceptable and, substantiallynon-toxic may be employed when using the (cis-1,2-epoxypropyl)phosphonicacid as an antibacterial agent. Other salts which are not nomallyemployed in pharmaceutical applications are useful as intermediates informing the free acid and for making other salts by metathesis. Inaddition, the salts with optically active amines may be employed asintermediates in resolving the (cis-1,2-epoxypropyl) phosphonic acidinto its optically active stereoisomers.

Where a halogen-substituted (sis-1,2-epoxypropyl)phosphonic acid isobtained upon oxidation, i.e., where a compound of Formula I is oxidizedwherein Y represents a halogen atom, such product is converted to(sis-1,2- epoxypropyl)phosphonic acid salts by alkaline hydrolysis. Thefree acid may then be converted to a more easily recoverable salt bytreatment with a less soluble metal salt such as calcium acetate wherebythe calcium salt of (cis-1,2-epoxypropyl)phosphonic acid precipitatesfrom the aqueous solution.

In those instances where compounds correspondin to Formula I, wherein Yrepresents OR are oxidized, the corresponding(cis-1,2-epoxypropyl)phosphonic acid ester is obtained. These esters maybe converted to salts of (cis 1,2-epoxypropyl)phosphonic acid by anumber of methods such as, for example, by photochemical reaction,hydrolysis with base and/ or acid, hydrogenolysis, conversion to atrimethylsilyl derivative and hydrolysis thereof and the like. Theoptimal method in any given instance depends upon the particular esterinvolved and representative examples appear in the experimental portionhereof.

In addition to oxidizing (cis-l,2-epoxypropyl)phosphonous acid compoundsof Formula I to yield the corresponding antibacterially active(cis-1,2-epoxypropyl) phosphonic acid compound, the compounds of FormulaI may be resolved, if desired, into the and enantiomers thereof, as byformation of a salt with an optically active amine such asa-phenethylamine, separation of the diastereoisomers of such salt byfractional crystallization and recovery of the and (1+) enantiomers of(cis-1,2-epoxypropyl)phosphonous acid. The separated enantiomers maythen be subjected to oxidation as described above to obtain and(!+)(cis-1,2-epoxypropyl)phosphonic acid compounds. The antibioticactivity resides in ()(cis-1,2-epoxypropyl)phosphonic acid so that thisacid and its salts possess essentially twice the antibacterial activity(on a weight basis) of the (cis- 1,2-epoxypropyl)phosphonic acidcompounds.

The method utilized to resolve (cis 1,2 epoxypropyl) phosphonous acidinto its optically active forms prior to oxidation is not part of thepresent invention, but is an invention being claimed in anotherco-pending application of the assignee.

The preparation of the starting materials of the process of thisinvention, i.e. compounds of Formula I, is given in detail in thefollowing examples. In general, however, a compound having the formulaeCH3 CH=CHP CHrC 11:0 11- I Y II IIA wherein X, R and Y are definedabove, is treated with an acylating agent such as acetyl chloride,propionyl chloride, butyryl chloride and the like, to thereby obtain acompound having the formula III 2: Q

wherein X and Y are defined above and Q represents an acyl group, i.e.an alkanoyl or aroyl group. Epoxidation of a compound of Formula IIIafiords a compound having the formula wherein X, Q and Y are definedabove.

Deacylation of the compounds represented by Formula IV yield thesatrting materials of the present invention which are illustrated byFormula I above.

More particularly, dibutyl cis-l-propenylphosphonite is prepared byreaction of l-propenyl magnesium bromide and dibutyl chlorophosphite.The treatment of dibutyl cisl-propenylphosphonite with acetyl chlorideyields (i) acetyl-butyl cis 1 propenylphosphonate which, when treatedwith hydrogen peroxide and sodium tungstate, affords (:)acety1-butyl(cis-1,2-epoxypropyl) phosphonate. Alkaline hydrolysis of the lattercompound yields (i) sodium (cis-1,2-epoxypropyl)phosphonite.

Alternatively, the starting materials of Formula I are prepared, forexample, by acidic hydrolysis of a diester of cz's-l-propenylphosphonousacid, e.g. di-n-butyl-cis-lpropenylphosphonite, such as by treatmentwith hydrochloric acid in n-propanol and neutralizing with benzylamine.In this manner there is obtained cis-l-propenylphosphonous acid,benzylammonium salt which is then epoxidized using, for example,hydrogen peroxide and so d1um tungstate to afford(i)(cis-1,2-epoxypropyl)phosphonous acid, benzylammonium salt. Thelatter compound is then oxidized as described above to yield (i)(c1iir-1,2-epoxypropyl) phosphonic acid, benzylammonium sa Additionally,the starting materials are prepared by reduction of O,S-dialkyl-(cis 1,2epoxypropyl)phosphonthioates. Thus, 1 g. of a (i) or(-)0,S-dialkyl(cis-l,2- epoxypropyl)phohsphonthioate is contacted with200 mg. of deactivated Raney nickel in 20 ml. of dioxane. After 3 hoursthe mixture is filtered and alkyl (-3) or (-)(cis-1,2-epoxypropyl)phosphonite is recovered and the solution is basifiedwith sodium hydroxide to afford sodium (i) or(cis-1,2-epoxypropyl)phosphonite.

Specific embodiments of the invention are described in the followingexamples. It is to be understood, however, that the examples are merelyfor purposes of illustration and it is not intended that the scope ofthe invention be limited thereby.

EXAMPLE 1 Dibutyl-l-propenyl phosphonite A solution of l-propenylmagnesium bromide in 250 ml. of tetrahydrofuran is prepared from 30.6 g.of l-bromopropene (cis/trans ratio 2:1) and 7 g. of magnesium. Thesolution is cooled to 40 C. and stirred during the addition of 54 g. ofdibutyl-chlorophosphite in ml. of tetrahydrofuran during a period of 10minutes. The temperature is kept below -30 C. with the aid of a Dry Icebath. The solution is stirred at room temperature for 3 hours and 56 g.of dry pyridine are then added with slight cooling. The pyridinemagnesium bromide is filtered off, washed with 50 ml. of tetrahydrofuranand the combined filtrate is evaporated under reduced pressure to asyrup. The syrup is extracted with 300 ml. of petroleum ether which isdecanted and evaporated. The residual oil is distilled to yield 30 g. ofa cis-trans mixture of dibutyl-1- propenyl phosphonite, b.p. 74/l mm.The cis and trans isomers are separated by fractional distillation.

EXAMPLE 2 Acetyl-butyl cis-l-propenyl phosphonate Di-n-butylcis-propenyl phosphonite (109 g.) is added dropwise to 39.2 g. acetylchloride keeping the temperature of the reaction mixture below 30 C. bymeans of an external ice bath. The addition is completed in about 45minutes. The reaction mixture is allowed to stand for 15 hours at roomtemperature, after which the n-butyl chloride which forms during thereaction is removed in vacuo, leaving acetyl-butyl cis-l-propenylphosphonate.

In a similar fashion, acetyl-ethyl cis-propenyl phosphonate,propionyl-butyl cis-propenyl phosphonate, butyryl-butyl cis-propenylphosphonate are prepared by utilization of propionyl chloride andbutyryl chloride in place of acetyl chloride.

EXAMPLE 3 (:)Acetyl-butyl(cis-1,2-epoxypropyl)phosphonate One gram ofacetyl-butyl cis-l-propenylphosphonate is treated with an aqueoussolution of 1.0 ml. 30% hydrogen peroxide and 20 mg. of sodium tungstatewhile maintaining a pH of 6.0. The reaction mixture is heated in a waterbath at 60 C. for one hour. One hundred milligrams of manganese dioxideare then added to decompose excess peroxide and the suspension isfiltered to give a solution of (i)acetyl-butyl(cis-1,2-epoxypropyl)phosphonate.

7 EXAMPLE 4 Preparation of sodium(cis-l,2-epoxypropyl)phosphonite Whilemaintaining a pH of 10.5, 2.5 N sodium hydroxide is added dropwise tothe solution of (i)acetylbutyl(cis-l,2-epoxypropyl)phosphonate preparedin Example 3. The sodium hydroxide is slowly consumed and uptake ceaseswhen 2 equivalents are added. The solution is lyophilized to yieldsodium(cis-l,2-epoxypropyl)phosphonite.

EXAMPLE 5 Sodium i) (cis-1,2-epoxypropyl)phosphonate One gram ofsodium(:) (cis-1,2-epoxypropyl)phos phonite is treated with an aqueoussolution of 1.0 ml. of 30% hydrogen peroxide and 20 mg. of sodiumtungstate while maintaining a pH of 6.0. The reaction is heated in awater bath at 40 C. for two hours. One hundred milligrams of manganesedioxide are then added to decompose excess hydrogen peroxide and themixture is filtered to afford a solution of sodium(:)(cis-1,2-epoxypropyl) phosphonate.

EXAMPLE 6 Sodium (cis-1,2-epoxypropyl)phosphonate Two grams ofsodium()(cis-LZ-epoxypropyl)phosphonite are treated with an aqueoussolution of bromine (1.1 equivalents) for 3 hours at 40 C. whilemaintaining a pH of 6.0 and the solution is evaporated to afford sodium(cis-1,2-epoxypropyl)phosphonate.

EXAMPLE 7 Potassium(i) (cis-1,2-epoxypropyl)phosphonate One gram ofpotassium (:)(cis-1,2-epoxypropyl) phosphonite is treated with anaqueous solution of 1.0 ml. of 30% hydrogen peroxide while maintaining apH of 6.0. The reaction is heated in a water bath at 40 C. for twohours. One hundred milligrams of manganese dioxide are then added todecompose excess hydrogen peroxide and the mixture is filtered to alforda solution of potassium( (cis-1,2-epoxypropyl) phosphonate.

EXAMPLE 8 'Sodium(i) (cis-1,2-epoxypropyl) phosphonate Two grams ofsodium(:)'(cis-1,2-epoxypropyl)phos phonite is treated with a methanolicsuspension of .111 equivalents of freshly prepared silver oxide. Thereaction is stirred and heated for 3 hours at 40 C., filtered andevaporated in vacuo to afford sodium(i)(cis-1,2-epoxypro pylphosphonate.

EXAMPLE 9 sodium( i) (cis-1,2-epoxypropyl)phosphonate One gram ofsodium(cis-l,2-epoxypropyl)phosphonite is treated with 1.1 equivalentsof an ethanolic solution of perphthalic acid. The reaction mixture isheated for four hours at 20 'C., extracted and concentrated to affordsodium( (cis-1,2-epoxypropyl) phosphonate.

EXAMPLE 10 sodium( i cis-l ,2-epoxypropyl) phosphonate One gram ofchloro(cis-1,2-epoxypropyl)phosphonite is treated with 1.!1 equivalentsof peroxytrifluoroacetic acid in 20 ml. of methylene chloride and thesolution is allowed to stand for 8 hours at 10 C., while maintaining thepH at 6.0. The solution is then basified with sodium hydroxide, filteredand evaporated in vacuo to afford sodium)'(cis-1,Z-epoxypropyl)phosphonate.

EXAMPDE 11 Sodium'( (cis-1,2-epoxypropyl) phosphonate One gram ofbenzyl(cis-1,2-epoxypropyl)phosphonite in 30 ml. ethanol is treated withan aqeous solution of 1.0

ml. of 30% hydrogen peroxide and 30 mg. of sodium tungstate whilemaintaining a pH of 6.0. The reaction is heated in a water bath for twohours at 40 C. One hundred milligrams of manganese dioxide are added andthe mixture is filtered to afford a solution of benzyl(i)- (cis1,2-epoxypropyl)phosphonate. The solution is then treated with 250 mg.of 10% Pd/ C and shaken with 40 p.s.i. of hydrogen at room temperaturefor '15 minutes. The reaction is then filtered and basilfied with sodiumhydroxide and concentrated to afford sodium(:) (cis- 1,2 epoxypropylphosphonate.

In a similar .manner, other (cisd,2-epoxypropyl)phosphonic acid estersare prepared. The ester is converted to the free acid or a salt thereofby appropriate procedures described hereinafter.

EXAMPLE 12 sodium(: (cis-l1,'2-epoxypropyl) phosphonate Ammonium'()'-(cis-l ,2-epoxypropyl) phosphonite (0.2 mole) is dissolved in 500 ml.of anhydrous methanol at 5 C. T o the solution there is added 0.2 moleof aphenethylamine hydrochloride and the methanol completely removed invacuo at less than 35 C. in a nitrogen atmosphere to afford (j:)u-(+)-phenethyl-ammonium(cis-l,2-epoxypropyl)phosphonite mixed withammonium chloride. Isopropanol ("125 ml.) is added, the mixture heatedto reflux and then filtered while hot. The filtrate is cooled to 25 C.and the product filtered, washed with isopropanol and air-dried at 25 C.to afford a-( phenethylammoniu'm(-)(cis 1,2 epoxypropyl)phosphonitehaving a high degree of optical purity.

The diastereomer, a phenethylammoniunr(+)- l (cis 1,2-epoxypropyl)phosphonite, is obtained by concentrating the mother liquors, filteringthe crystalline precipitate and Washing with 10 ml. of very coldisopropanol.

Each of the diastereomers is then subjected to oxidation in accordancewith the procedure of Example 5. ot'(|)- Phenethylammonium ()(cis 1,2epoxypropyl)ph-os phonate is then treated with one equivalent of sodiumhydroxide, extracted and concentrated to affordsodiumcis-1,2-epoxypr0pyl) phosphonate.

When the oxidation process of the invention leads to an ester of (i)(cis-1,2-epoxypropyl)phosphonic acid, such ester may be converted to thefree acid or preferably to a salt by one of several methods, the methodof choice depending upon the nature of the ester moiety .to be removed.

Thus, when R represents alkenyl, alkynyl or aralkyl moieties, thepreferred method for removing them is by hydrogenolysis, as by thefollowing procedure:

A solution of 3.2 g. of ;)dibenzyl(cis-1,2repoxypro pyl)phosphonate in250 ml. of methanol is hydrogenated at 40 p.s.i. at room temperature for15 minutes in the presence of 800 mg. of 10% palladium-on-charcoalcatalyst and 2 g. of potassium bicarbonate. The solution is filteredfrom the catalyst and evaporated to dryness in vacuo at room temperatureto yield (:)potassiun1 (cis- 1,2-epoxypropyl)phosphonate.

When R is lower alkyl or aryl, the preferred method for removing thesegroups is by ultraviolet light irradiation in the presence of base or byalkaline hydrolysis as exemplified below:

A solution of 4 g. of diphenyl( (cis-1,2-epoxypropyl) phosphonate in1100 ml. of an aqueous 2% solution of trimethylammonium carbonate isirradiated in a quartz flask at 25-30 C. for 4 hours with an ultravioletlight source. The solution is evaporated to dryness and the residueextracted into anhydrous methanol. The solution is then passed over asulfonic acid resin column (IR- previously dehydrated with methanol) onthe hydrogen cycle at 05 C. The efiluent is collected and rapidlyadjusted with cyclohexylamine to pH 5. Concentration of the solution todryness affords +)(cis-1,2-epoxypropyl) phosphonic acidmonocyclohexylamine salt.

A solution of 7 g. of *-)diethyl(cis-1,2-epoxypropyl) phosphonate in 75ml. of 2% trimethylammonium carbonate solution in a quartz flask isirradiated with an ultraviolet light source for 2 hours at 25-30 C.[Five milliliters of trimethylamine are added and the solution isevaporated to dryness in vacuo. The resulting product is crystallizedfrom alcohol to afford(:)bis-trimethylammoniurrt(cis-1,2-epoxypropyl)phosphonate.

Substituted alkyl and aryl esters are preferably hydrolyzed with basesuch as an alkali or alkaline earth metal hydroxide or oxide.Representative conditions are:

(:)Bis-acetoxymethyl(cis 1,2 epoxypropyl)phosphonate (0.1 mole) isdissolved in 50 ml. of water and then 0.1 mole of calcium oxide isadded. The solution is heated with stirring at 20-30 C. for 2 hours. Itis then concentrated to dryness in vacuo to give a residue of(:)calcium(cis-1,2-epoxypropyl)phosphonate.

A solution of 50 mm. of (i)diphenyl(cis-1,2-epoxypropyl)phosphonate inml. of 30% ethanol-water is refluxed with a two-fold excess of bariumhydroxide in a nitrogen atmosphere for 1 hours. The reaction is cooled,adjusted to pH 8 with 4N sulfuric acid and extracted 3 times with ethylacetate. The remaining aqueous slurry is stirred overnight at roomtemperature with 30 g. of sodium sulfate. The solids are removed byfiltration and the filtrate evaporated to dryness to give (1:) (cis-1,2-epoxypropyyl)phosphonic acid disodium salt.

Where R represents aryl or substituted aryl, the conversion to salts isconveniently efiected by treatment with sodium in a tertiary amine, Le,a solution of 5 g. of

(i)diphenyl(cis 1,2 epoxypropyl)phosphonate in 5 ml. of methanol isadded to ml. of trimethylamine. Small pieces of sodium are graduallyadded to a total of 2.0 g. The solvents are removed by concentration andthe product is extracted into methanol. The methanol solution is thenpassed over a column of IR- resin on the hydrogen cycle which has beenprecooled to 5 C. The efiluent is then basified to pH 8.2 withphenethylamine and concentrated to give (i)(cis 1,2epoxypropyl)phosphonic acid as the bis-phenethylamine salt.

Obviously, many modifications and variations of the present inventionare possible in the light of the above teachings. It is therefore to beunderstood that, within the scope of the appended claim, the inventionmay be practiced otherwise than as specifically described.

Having thus described the invention, what is claimed and desired to besecured by Letters Patent of the United States is:

1. Acetyl-butylcis-l-propenyl phosphonate.

References Cited UNITED STATES PATENTS 3,456,039 7/1969 Beriger et al260941 X ANTON H. SUTIO, Primary Examiner U.S. Cl. X.R.

